Excellence in Research: Developmental regulation of WDR77 coordinates prostate growth and differentiation during the development through puberty

卓越研究：WDR77 的发育调节可协调青春期发育期间的前列腺生长和分化

• 批准号: 2300390
• 负责人: Zhengxin Wang
• 金额: $ 91.4万
• 依托单位: Clark Atlanta University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2300390&HistoricalAwards=false
• 关键词: Excellence; Research; Developmental; regulation; WDR77

This research will address how altered male hormone levels during development through puberty affect growth and differentiation of the prostate gland. The project will first determine whether male hormone at lower levels (during puberty) leads to growth of the prostate gland and, in contrast, if higher levels of the male hormone (post-puberty) promote the prostate’s differentiation. The research will then investigate how the male hormone’s action is switched during prostate development throughout puberty. The proposed research represents a novel study concept that relates to the basic biology of prostate development. The various age-related diseases in older adult prostate reflect the loss of developmental coordination of cell proliferation and differentiation. Therefore, the research may also help to understand the development of various prostatic diseases in older men. The project will also directly support graduate and undergraduate student training and promote scientific research in a minority population at this HBCU.The mammalian prostate gland passes through several phases of rapid growth and differentiation during development. The molecular mechanisms that determine growth and differentiation stages, as well as coordinating these two processes are less defined. This research will address these critical questions. The goal of the project is to study molecular events and mechanisms that coordinate cell growth and differentiation during prostate development from adolescent (proliferating) to young adult (quiescent/differentiated) stage. The research will first investigate the androgen function in a dosage-dependent manner to control growth and differentiation of the prostate during mouse development through puberty. A concentration threshold at which the androgen action is switched from growth promotion to growth inhibition/differentiation will be determined. Previous studies have identified the WDR77 protein localized in the cytoplasm at the early (during puberty, proliferating) stage of the prostate development drives cell proliferation. In adult (post-puberty, quiescent/differentiated) prostate, the protein in the nucleus functions as an androgen receptor cofactor to promote cell differentiation. The research will then investigate whether WDR77 mediates the androgen’s role to coordinate growth and differentiation during the prostate development. How change of androgen levels alters epigenetic modifications, leading to altered expression of AR-target genes as well as WDR77 subcellular localization will be studied using chromatin immunoprecipitation and gene promoter mapping.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这项研究将解决通过青春期发育过程中雄性骑马水平改变的影响，影响前列腺的生长和分化。该项目将首先确定较低水平（青春期）的雄性骑马是否会导致前列腺的生长，相比之下，如果较高的雄性骑马（Puberty）较高水平，则可以促进前列腺的分化。然后，该研究将调查在整个青春期期间前列腺发育期间，男性骑马的行动如何转变。拟议的研究代表了一个与前列腺发展基本生物学有关的新型研究概念。老年人前列腺中与年龄相关的各种疾病反映了细胞增殖和分化的发育协调丧失。因此，这项研究还可能有助于了解老年男性各种前列腺疾病的发展。该项目还将直接支持研究生和本科生培训，并在此HBCU的少数族裔人群中促进科学研究。哺乳动物前列腺经过了多个在发育过程中快速增长和分化的阶段。确定生长和分化阶段以及协调这两个过程的分子机制的定义较低。这项研究将解决这些关键问题。该项目的目的是研究从青春期（增殖）到年轻成人（Quiestcent/分化）阶段的前列腺发育过程中的细胞生长和分化的分子事件和机制。该研究将首先以剂量依赖性的方式研究雄激素功能，以控制小鼠通过青春期发育过程中前列腺的生长和分化。将确定雄激素作用从生长促进转变为生长抑制/分化的浓度阈值。先前的研究已经确定了在早期（青春期，增殖期间）前列腺发育阶段局部在细胞质中局部的WDR77蛋白，驱动细胞增殖。在成年人（Puberty，静止/分化后）前列腺中，核功能中的蛋白质是雄激素受体辅助因子，以促进细胞分化。然后，该研究将研究WDR77是否介导了雄激素在前列腺发育过程中协调生长和分化的作用。 How change of androgen levels alters epigenetic modifications, leading to altered expression of AR-target genes as well as WDR77 subcellular localization will be studiod using chromatin immunoprecipitation and gene promoter mapping.This award reflects NSF's statutory mission and has been deemed honestly of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.